NAC1 Modulates Autoimmunity by Suppressing Regulatory T Cell-Mediated Tolerance Institutional Repository Document uri icon


  • AbstractFoxP3+ regulatory T cells (Tregs) are a distinct subset of CD4+ T cells integral to the maintenance of the balance of the immune system, and their dysregulation is a trigger of autoimmunity. We report here that nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the broad complex, tramtrack, bric-a-brac / poxvirus and zinc finger (BTB/POZ) gene family, is a negative regulator of FoxP3 in Tregs and a critical determinant of immune tolerance. Phenotypically, NAC1-/- mice show substantial tolerance to the induction of autoimmunity, as evidenced by the significantly decreased occurrences of autoimmune arthritis and colitis. Analysis of T cells from the wild-type (WT) or NAC1 knockout (-/-) mice found that NAC1 is crucially involved in the early stage of T cell development. NAC1 positively affects CD8+ T cell differentiation, but negatively regulates Treg development. Compared with WT animals, NAC1-/- mice displayed defects in CD8+ T cell development but generated a larger amount of CD4+ regulatory Tregs that exhibit a higher metabolic profile and immune suppressive activity, increased acetylation, and expression of FoxP3, and slower turnover of this transcriptional factor. Furthermore, treatment of Tregs with the pro-inflammatory cytokines IL-1 or TNF- induced a robust upregulation of NAC1 but an evident downregulation of FoxP3 as well as the acetylated FoxP3, suggesting that the reduction of FoxP3 by the NAC1-mediated deacetylation and destabilization of this lineage-specific transcriptional factor contributes considerably to break of immune tolerance. These findings imply that the pro-inflammatory cytokines-stimulated upregulation of NAC1 acts as a trigger of the immune response through destabilization of Tregs and suppression of tolerance induction, and that therapeutic targeting of NAC1 warrants further exploration as a potential tolerogenic strategy for treatment of autoimmune disorders.

altmetric score

  • 0.75

author list (cited authors)

  • Yang, J., Ren, Y., Kumar, A., Xiong, X., Das, J. K., Peng, H., ... Song, J.

citation count

  • 0

complete list of authors

  • Yang, Jin-Ming||Ren, Yijie||Kumar, Anil||Xiong, Xiaofang||Das, Jugal Kishore||Peng, Hao-Yun||Wang, Liqing||Ren, Xingcong||Zhang, Yi||Ji, Cheng||Cheng, Yan||Zhang, Li||Alaniz, Robert C||de Figueiredo, Paul||Fang, Deyu||Liu, Xiaoqi||Wang, Jianlong||Song, Jianxun

Book Title

  • bioRxiv

publication date

  • March 2022